Known processes for producing an optically active L- or D-α-methylcysteine derivative or its salt include the following:
1) A process asymmetric methylation of an optically active thiazolidine compound produced from optically active cysteine and pivalaldehyde (WO01/72702).
2) A process of asymmetric thiomethylation of an optically active oxazolone compound produced from optically active alanine and benzaldehyde (J. Org. Chem., 1996, 61, 3350-3357).
3) A process of methylation of a thiazoline compound produced from cysteine and cyanobenzene, and isolating and purifying the resulting racemic thiazoline compound by chiral HPLC (Synlett., 1994, 9, 702-704).
4) A process of asymmetric bromomethylation of an optically active diketopiperazine compound synthesized from optically active valine and alanine, and replacement of the bromine atom of the resulting compound by an alkali metal alkylthiolate (Synthesis, 1983, 37-38).
5) A process for the reaction of thiol with the optically active aziridine which is prepared from the optically active 2-methylglycidol obtained by Sharpless asymmetric oxidation of 2-methyl-2-propene-1-ol (J. Org. Chem., 1995, 60, 790-791).
6) A process of methylation of aminomalonic acid derivatives, desymmetrization of the product with pig liver esterase (abbreviated as “PLE” hereinafter), and reaction of the resulting asymmetric ester with an alkali metal thioacetate (J. Am. Chem. Soc., 1993, 115, 8449-8450).
Any of processes 1) to 4) requires low-temperature reaction with an expensive base such as butyl lithium. Process 5) is complicated by a large number of steps, and requires various kinds of expensive reagents. The key step of process 6) is the desymmetrization of the diester by PLE as esterase etc., but PLE cannot be easily stably secured on an industrial scale because of difficulty in mass production of PLE, thereby making the process unpractical. Therefore, any one of the processes has problems to be solved as an industrial process for producing an optically active methylcysteine derivative or its salt.
The optically active methylcysteine derivative produced by any one of the above-described processes and the like(,) can be converted to optically active α-methylcysteine or its salt by appropriate deprotection if necessary. The resulting optically active α-methylcysteine or its salt is preferably isolated and purified by crystallization. However, there has been no known example of isolation of optically active α-methylcysteine or its salt by crystallization. Only the above-described WO01/72702 etc. disclose examples of isolation. These examples relate to a method in which a thiazolidine compound which is an optically active α-methylcysteine derivative is deprotected with hydrochloric acid, resulting an aqueous solution of optically active α-methylcysteine or its salt is concentrated to produce a solid, and in some cases, the solid is washed with an organic solvent to isolate the compound. However, as a result of isolation of the compound according to this method, the inventors have found that a solid is precipitated with concentration of the aqueous solution, and at the same time, the solid becomes a large lump containing water to make stirring difficult. Also, when concentration is continued, the solid strongly adheres to the wall and comes to a non-fluid state. Therefore, the operation of concentrating the aqueous solution to precipitate a solid is disadvantageous as an industrial operation, and the solid tends to be aggregated with concentration. This causes difficulty in stirring a crystallization solution and isolating the solid. Therefore, the isolation methods disclosed in the above WO01/72702 etc. are unsuitable for industrial production.
Furthermore, if the insoluble inorganic salts generate and are mixed in the optically active α-methylcysteine or its salt obtained by deprotection of optically active methylcysteine derivative during the reaction or a post-treatment step like neutrization etc., the inorganic salt cannot be removed by the above-described conventional method.
Furthermore, α-methylcysteine or its salt is unstable against oxidation and is easily converted to a disulfide by dimerization. For example, dimerization of cysteine having a similar structure rapidly proceeds to produce cystine (Protein Chemistry 1, Amino Acid Peptide, Kyoritsu Shuppan, p. 326). Also, dimerization of α-methylcysteine proceeds to produce a disulfide, and the disulfide cannot be easily removed and is unavoidably mixed in a product. Therefore, it is important to establish a process capable of significantly suppressing the production and mixing of a disulfide.
It is thus strongly demanded to establish an industrially practical process for appropriately crystallizing a high-quality optically active α-methylcysteine or its salt to obtain the compound as crystals.
Apart from the conventional processes, a conceivable process for simply producing an optically active α-methylcysteine derivative is to convert a racemic α-methylcysteine derivative to an optically active α-methylcysteine derivative by enzymatic resolution. In order to realize this method, it is important to establish a process for producing a racemic α-methylcysteine derivative to be supplied to optical resolution and enzymatic reaction having high optical resolution ability. It is also important to properly select a racemic α-methylcysteine derivative to be supplied to the enzymatic optical resolution.
In order to realize the process using enzymatic optical resolution, it is required that a racemic α-methylcysteine derivative used as a substrate can be simply effectively produced, conforms to the substrate specificity of an enzyme, and has a protecting group or an auxiliary group suitable for achieving high stereoselectivity, and the protecting group or auxiliary group can be simply removed after enzymatic reaction. From this viewpoint, a preferred racemic α-methylcysteine derivative is an N-carbamoyl-α-methylcysteine derivative.
It has been known for a long time that hydantoinase known as a hydrolase for ring opening of hydantoin also catalyzes a reverse reaction of converting N-carbamoyl-α-amino acid to corresponding 5-substituted hydantoin. It is thus expected that one of the optical isomers of the racemic N-carbamoyl-α-methylcysteine derivative is selectively converted to hydantoin with the enzyme and subjected to optical resolution. The optically active N-carbamoyl-α-methylcysteine derivative obtained by optical resolution can easily be converted to an optically active α-methylcysteine derivative by decarbamoylation. The other product of the optical resolution, i.e., an optically active 5-methyl-5-thiomethylhydantoin derivative, is equivalent to an optically active α-methylcysteine derivative and can thus be led to an optically active α-methylcysteine derivative (having a configuration reverse to that of the product directly obtained by optical resolution) through ring-opening hydrolysis and decarbamoylation.
The racemic N-carbamoyl-α-methylcysteine derivative can be produced by combination of a general chemical method for synthesizing an amino acid and N-carbamoylation reaction. However, a process for producing the racemic N-carbamoyl-α-methylcysteine derivative in a small number of steps and high yield has not yet been established.
A known example of a general process for producing a racemic N-carbamoyl-α-disubstituted amino acid comprises converting an acetone derivative to racemic 5,5-disubstituted hydantoin by the Bucherer method, hydrolyzing the racemic 5,5-disubstituted hydantoin to produce a racemic α-disubstituted amino acid derivative (Agr. Biol. Chem., 1971, 35, 53-58), and then N-carbamoylating the derivative by treatment with potassium cyanate. However, in this method, the ureylene group (—NHCONH—) of the racemic 5,5-disubstituted hydantoin cannot be effectively used as the ureido group (carbamoylamino group: —NHCONH2) of the racemic N-carbamoyl-α-disubstituted amino acid derivative. Also, the method requires the three steps and is thus inefficient.
On the other hand, as a method for producing a carbamoyl compound without passing through an amino acid produced by hydrolysis of hydantoin, a method of hydrolyzing with calcium hydroxide used as a base is known (U.S. Pat. No. 5,338,859). However, as a result of production of a racemic N-carbamoyl-α-methylcysteine derivative according to this method, the inventors found that the target compound can be obtained in only 25% yield. Namely, a process for producing a racemic N-carbamoyl-α-disubstituted amino acid derivative, particularly a racemic N-carbamoyl-α-methylcysteine derivative, in a small number of steps and high yield has not yet been established.
On the other hand, with respect to enzymatic optical resolution of a racemic N-carbamoyl-α-methylcysteine derivative, Japanese Unexamined Patent Application Publication No. 1-124398 discloses a resolution process in which a racemic N-carbamoyl-amino acid derivative is stereoselectively cyclized by treatment with hydantoinase. However, the possibility of reaction of an N-carbamoyl-α-methylcysteine derivative is neither disclosed nor suggested.